Malishev Ravit, Nandi Sukhendu, Kolusheva Sofiya, Levi-Kalisman Yael, Klärner Frank-Gerrit, Schrader Thomas, Bitan Gal, Jelinek Raz
Department of Chemistry, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.
Ilse Katz Institute for Nanotechnology, Ben Gurion University of the Negev , Beer Sheva 84105, Israel.
ACS Chem Neurosci. 2015 Nov 18;6(11):1860-9. doi: 10.1021/acschemneuro.5b00200. Epub 2015 Sep 9.
Although the precise molecular factors linking amyloid β-protein (Aβ) to Alzheimer's disease (AD) have not been deciphered, interaction of Aβ with cellular membranes has an important role in the disease. However, most therapeutic strategies targeting Aβ have focused on interfering with Aβ self-assembly rather than with its membrane interactions. Here, we studied the impact of three toxicity inhibitors on membrane interactions of Aβ42, the longer form of Aβ, which is associated most strongly with AD. The inhibitors included the four-residue C-terminal fragment Aβ(39-42), the polyphenol (-)-epigallocatechin-3-gallate (EGCG), and the lysine-specific molecular tweezer, CLR01, all of which previously were shown to disrupt different steps in Aβ42 self-assembly. Biophysical experiments revealed that incubation of Aβ42 with each of the three modulators affected membrane interactions in a distinct manner. Interestingly, EGCG and CLR01 were found to have significant interaction with membranes themselves. However, membrane bilayer disruption was reduced when the compounds were preincubated with Aβ42, suggesting that binding of the assembly modulators to the peptide attenuated their membrane interactions. Importantly, our study reveals that even though the three tested compounds affect Aβ42 assembly differently, membrane interactions were significantly inhibited upon incubation of each compound with Aβ42, suggesting that preventing the interaction of Aβ42 with the membrane contributes substantially to inhibition of its toxicity by each compound. The data suggest that interference with membrane interactions is an important factor for Aβ42 toxicity inhibitors and should be taken into account in potential therapeutic strategies, in addition to disruption or remodeling of amyloid assembly.
尽管将淀粉样β蛋白（Aβ）与阿尔茨海默病（AD）联系起来的确切分子因素尚未被破解，但Aβ与细胞膜的相互作用在该疾病中起着重要作用。然而，大多数针对Aβ的治疗策略都集中在干扰Aβ的自我组装上，而不是其与膜的相互作用。在此，我们研究了三种毒性抑制剂对Aβ42（Aβ的较长形式，与AD关联最为紧密）膜相互作用的影响。这些抑制剂包括四肽C末端片段Aβ(39 - 42)、多酚（-）-表没食子儿茶素-3-没食子酸酯（EGCG）以及赖氨酸特异性分子钳CLR01，所有这些之前都被证明可破坏Aβ42自我组装的不同步骤。生物物理实验表明，Aβ42与这三种调节剂中的每一种孵育都会以独特的方式影响膜相互作用。有趣的是，发现EGCG和CLR01自身与膜有显著相互作用。然而，当这些化合物与Aβ42预孵育时，膜双层破坏减少，这表明组装调节剂与肽的结合减弱了它们与膜的相互作用。重要的是，我们的研究表明，尽管这三种测试化合物对Aβ42组装的影响不同，但每种化合物与Aβ42孵育后，膜相互作用都被显著抑制，这表明阻止Aβ42与膜的相互作用对每种化合物抑制其毒性有很大贡献。数据表明，干扰膜相互作用是Aβ42毒性抑制剂的一个重要因素，除了破坏或重塑淀粉样蛋白组装外，在潜在的治疗策略中也应予以考虑。
